The most common secretory hypothalamic-pituitary disorders encountered in clinical reproductive endocrinology are those associated with hyperprolactinemia. Hyperprolactinemia accounts for at least 20% of infertility in women and at least 8% of sexual dysfunction in men, including infertility. The etiologies of pathological hyperprolactinemia are diverse, but by far the most common cause is a pituitary tumor. The pathogenesis of prolactinomas has yet to be defined. Since most prolactin (PRL)-secreting tumors occur in premenopausal women and exhibit growth in the presence of estrogens, the rat model of diethylstilbestrol (DES)-induced tumors is an excellent model for the study of the mechanism of prolactinoma formation. Several studies revealed intrapituitary vasoactive intestinal polypeptide (VIP) tissue content and mRNA increases significantly in these estrogen-induced rat prolactinomas. Additionally, exogenous and endogenous VIP is a well known stimulator of PRL release from pituitary tissue in vivo and in vitro. This laboratory found immunoneutralization of intrapituitary VIP with VIP antiserum (AVIP) significantly decreased PRL mRNA in dispersed rat DES tumor cells. The goal of this project is to focus on this relationship between estrogen and VIP in the formation of prolactinomas. The central hypothesis of this application is VIP plays an important intermediary role in the pathogenesis of DES-induced prolactinomas. The specific aims developed to test this hypothesis include: I. To determine if the significant reduction in rPRL mRNA from dispersed DES-induced prolactinoma cells incubated in AVIP is due to an effect on PRL gene transcription, mRNA degradation, or both. II. To determine if the significant reduction in rPRL mRNA from dispersed DES-induced prolactinoma cells incubated in AVIP is observed after longer periods of DES exposure. III. To determine how other known PRL regulators, TRH and dopamine, affect the anterior pituitary VIP tissue content and mRNA in the DES- induced tumor model. IV. To determine whether the formation of these estrogen-induced prolactinomas can be prevented by inhibition of VIP. Answers to these key questions will help to elucidate the pathogenesis of the most common neuroendocrine disorder, the prolactinoma, and to prevent its major clinical consequences; infertility, sexual dysfunction, osteopenia and visual impairment.